Benaliouad Faïza, Kapur Shitij, Rompré Pierre-Paul
Centre de recherche Fernand-Seguin, Hôpital Louis-H Lafontaine, Montréal, QC, Canada.
Neuropsychopharmacology. 2007 Mar;32(3):551-61. doi: 10.1038/sj.npp.1301136. Epub 2006 Jun 14.
Previous studies have shown that effective antipsychotic medications attenuate reward, an effect that is generally attributed to their effectiveness at blocking the dopamine D2-like receptors. As blockade of the serotonin type 2a (5-HT2a) receptors is a common property of the newer antipsychotics, the present study compared the effect of haloperidol, clozapine, and M100907 (a selective 5-HT2a antagonist) and the combined effect of haloperidol and M100907 treatment on brain stimulation reward (BSR). Experiments were performed on male Sprague-Dawley rats trained to produce an operant response to obtain electrical stimulation in the lateral hypothalamus. Measures of reward threshold were determined in different groups of rats using the curve-shift method using fixed current intensity and variable frequency before and at different times after injection of haloperidol (0.01, 0.05, 0.1, and 0.25 mg/kg), clozapine (1, 7.5, 15, and 30 mg/kg), M100907 (0.033, 0.1, and 0.3 mg/kg), or their vehicle. The effect of M100907 (0.3 mg/kg) on the attenuation of BSR by a sub- and suprathreshold dose of haloperidol was studied in another group of rats. Clozapine produced a dose-orderly increase in reward threshold with a mean maximal increase of 50%; at high doses, clozapine induced cessation of responding in several animals at different time periods. Haloperidol induced a dose-dependent increase in reward threshold, with the mean maximal increase (75%) being observed at the highest dose; it also produced a dose-dependent reduction of maximum rates of responding. M100907 failed to alter reward at any of the doses tested and had no effect on the subthreshold dose (0.01 mg/kg) of haloperidol. But when combined with a suprathreshold dose of haloperidol, M100907 reduced the reward-attenuating effect of haloperidol. These results show that 5-HT2a receptors are unlikely to constitute a component of the reward-relevant pathway activated by lateral hypothalamic stimulation. However, blockade of 5-HT2a receptors may account for the relatively lower level of reward attenuation produced by clozapine, and predict that antipsychotic medications that have a high affinity for the 5-HT2a receptor may be less likely to induce dysphoria.
以往的研究表明，有效的抗精神病药物会减弱奖赏效应，这种效应通常归因于它们阻断多巴胺D2样受体的有效性。由于阻断5-羟色胺2a（5-HT2a）受体是新型抗精神病药物的共同特性，因此本研究比较了氟哌啶醇、氯氮平和M100907（一种选择性5-HT2a拮抗剂）的作用，以及氟哌啶醇和M100907联合治疗对脑刺激奖赏（BSR）的影响。实验在雄性Sprague-Dawley大鼠身上进行，这些大鼠经过训练，能做出操作性反应以获得下丘脑外侧的电刺激。在注射氟哌啶醇（0.01、0.05、0.1和0.25mg/kg）、氯氮平（1、7.5、15和30mg/kg）、M100907（0.033、0.1和0.3mg/kg）或它们的溶媒之前及之后的不同时间，使用固定电流强度和可变频率的曲线移动法，在不同组大鼠中测定奖赏阈值。在另一组大鼠中研究了M100907（0.3mg/kg）对阈下和阈上剂量氟哌啶醇减弱BSR效应的影响。氯氮平使奖赏阈值呈剂量依赖性增加，平均最大增加50%；在高剂量时，氯氮平在不同时间段导致几只动物反应停止。氟哌啶醇使奖赏阈值呈剂量依赖性增加，在最高剂量时观察到平均最大增加（75%）；它还使最大反应率呈剂量依赖性降低。M100907在任何测试剂量下均未改变奖赏，且对氟哌啶醇的阈下剂量（0.01mg/kg）无影响。但当与阈上剂量的氟哌啶醇联合使用时，M100907降低了氟哌啶醇的奖赏减弱效应。这些结果表明，5-HT2a受体不太可能构成由下丘脑外侧刺激激活的奖赏相关通路的一个组成部分。然而，阻断5-HT2a受体可能解释了氯氮平产生的相对较低水平的奖赏减弱，并预测对5-HT2a受体具有高亲和力的抗精神病药物可能不太可能诱发烦躁不安。
